Molecular Mechanisms of Functional Adrenocortical Adenoma and Carcinoma: Genetic Characterization and Intracellular Signaling Pathway

Abstract

The adrenal cortex produces steroid hormones as adrenocortical hormones in the body, secreting mineralocorticoids, glucocorticoids, and adrenal androgens, which are all considered essential for life. Adrenocortical tumors harbor divergent hormonal activity, frequently with steroid excess, and disrupt homeostasis of the body. Aldosterone-producing adenomas (APAs) cause primary aldosteronism (PA), and cortisol-producing adenomas (CPAs) are the primary cause of Cushing’s syndrome. In addition, adrenocortical carcinoma (ACC) is a highly malignant cancer harboring poor prognosis. Various genetic abnormalities have been reported, which are associated with possible pathogenesis by the alteration of intracellular signaling and activation of transcription factors. In particular, somatic mutations in APAs have been detected in genes encoding membrane proteins, especially ion channels, resulting in hypersecretion of aldosterone due to activation of intracellular calcium signaling. In addition, somatic mutations have been detected in those encoding cAMP-PKA signaling-related factors, resulting in hypersecretion of cortisol due to its driven status in CPAs. In ACC, mutations in tumor suppressor genes and Wnt-β-catenin signaling-related factors have been implicated in its pathogenesis. In this article, we review recent findings on the genetic characteristics and regulation of intracellular signaling and transcription factors in individual tumors.

Identification of Key Genes and Related Drugs of Adrenocortical Carcinoma by Integrated Bioinformatics Analysis

“…transcription factors inhibits the transcriptional activity of MEN1, thereby contributing to tumor growth. Both of the above mechanisms have been confirmed as components of ACC pathogenesis [9]. Calcium ions play a crucial role in the synthesis and release of the adrenal cortex hormone, and alterations in the intracellular calcium ion concentration following cellular depolarization stimulate the production of hormones such as aldosterone [10].…”

Genetic Alterations in Benign Adrenal Tumors

“…Here, the majority of variants involved in APAs are deletions within a specific region of the M4 domain which is involved in binding of Ca 2+ and ion gating [115,116,118,122,123,126,127,140,145,146]. In vitro studies have shown that ATP2B3 variants increase production of aldosterone by decreasing export of Ca 2+ (due to loss of the pump function) leading to increased intracellular concentration of Ca 2+ , membrane depolarization, and activation of calcium signaling [147,148].…”

Research progress and perspectives of noncoding RNAs in adrenocortical carcinoma: A review

“…[13] Only a few patients with ACC are associated with familial genetic disorders, while disseminated cases are associated with mutations in various genes such as tumor protein p53, catenin beta like 1, menin 1, and cyclin dependent kinase inhibitor 2A. [17][18][19] However, the specific pathogenic mechanism of ACC remains unclear. Hence, exploring the diagnostic markers and therapeutic targets for ACC is urgent.…”